32P analysis of DNA adducts in tissues of benzene-treated rats.

Reddy, M V; Blackburn, Gary R.; Schreiner, Ceinwen A.; Mehlman, Myron A.; Mackerer, Carl R.

doi:10.1289/ehp.8982253

Cited by 31 publications

(17 citation statements)

References 22 publications

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“…In addition, animal studies have shown that after benzene exposure, increases in micronuclei, chromosome loss, and breakage are seen in the hematopoietic cells of mice and rats (1,4,5). These chromosomal effects, combined with observations that benzene is only weakly mutagenic in standard gene mutation assays (6,7) and binds poorly to DNA (8,9) suggest that indirect genetic mechanisms that result in translocations, deletions, aberrant recombination, or aneuploidy may be important in benzene's genotoxic effects (10,11). It is also likely that the chromosome damage seen in the blood cells of occupationally exposed populations reflects alterations occurring in the hematopoietic stem cells, which contribute to leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites.

Frantz

Chen

Eastmond

1996

Environ Health Perspect

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Benzene is a clastogenic and carcinogenic agent that induces acute myelogenous leukemia in humans and multiple types of tumors in animals. Previous research has indicated that benzene must first be metabolized to one or more bioactive species to exert its myelotoxic and genotoxic effects. To better understand the possible role of individual benzene metabolites in the leukemogenic process, as well as to further investigate inhibition of topoisomerase 11 by benzene metabolites, a series of known and putative benzene metabolites, phenol, 4,4'-biphenol, 2,2'-biphenol, hydroquinone, catechol, 1,2,4-benzenetriol, 1,4-benzoquinone, and trans-transmuconaldehyde were tested for inhibitory effects in vitro on the human topoisomerase 11 enzyme. With minor modifications of the standard assay conditions, 1,4-benzoquinone and transtrans-muconaldehyde were shown to be directly inhibitory, whereas all of the phenolic metabolites were shown to inhibit enzymatic activity following bioactivation using a peroxidase activation system. The majority of compounds tested inhibited topoisomerase 11 at concentrations at or below 10 pM. These results confirm and expand upon previous findings from our laboratory and indicate that many of the metabolites of benzene could potentially interfere with topoisomerase 11. Since other inhibitors of topoisomerase 11 have been shown to induce leukemia in humans, inhibition of this enzyme by benzene metabolites may also play a role in the carcinogenic effects of benzene. Environ Health Perspect 104(Suppl 6): 1319-1323 (1996)

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Section: Introductionmentioning

confidence: 99%

Inhibition of human topoisomerase II in vitro by bioactive benzene metabolites.

Frantz

Chen

Eastmond

1996

Environ Health Perspect

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“…Taken together, the data suggest that an adducted 3'-nucleotide with a carcinogen bound to a base at the exocyclic position, but not at the endocyclic position, is resistant to nuclease P -mediated dephosphorylation. When the attachment is simultaneously at the exocyclic and endocyclic positions, for example, a cyclic adduct, as in the case of the major adduct of BQ-DNA above, the adduct may not be susceptible to the enzyme activity (21). Such differential enzyme activity may be useful in adduct characterization.…”

Section: Discussionmentioning

confidence: 99%

A Method for In Vitro Culture of Rat Zymbal Gland: Use in Mechanistic Studies of Benzene Carcinogenesis in Combination with 32 P-Postlabeling

Reddy¹,

Blackburn²,

Irwin³

et al. 1989

Environmental Health Perspectives

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Zymbal glands were excised bilaterally from the ear ducts of female Sprague-Dawley rats (three/group), minced into approximately four fragments per gland, and transferred into a microtiter plate containing 1.5 mL per well of Waymouth's tissue culture medium supplemented with fetal calf serum, hydrocortisone, insulin, and gentamicin. After addition of a test compound or solvent vehicle, plates were incubated for 6, 24, 48, or 96 hr at 37°C in a humidified atmosphere of 5% CO2 in air. Tissue in culture for 6 hr was histologically indistinguishable from the freshly excised tissue, while that in culture for 24, 48, and 96 hr showed a progressive deterioration often with necrosis and/or squamous metaplasia. More pronounced deterioration was noted in samples treated with 750 or 1500 pg/mL of benzene. Using a nuclease Pi-enhanced 32P-postlabeling assay, aromatic DNA adducts were detected in cultured Zymbal glands exposed for 48 hr to benzene and its derivatives, as well as to 7,12-dimethylbenzanthracene (DMBA) and 2-acetylaminofluorene (AAF). Benzene produced very low levels of adducts (0.5 adducts per 109 nucleotides), whereas its congeners produced relatively high levels of adducts (50-2000 lesions per 109 nucleotides), which decreased in the order benzoquinone > hydroquinone > phenol > benzenetriol > catechol. Each adduct profile overall was characteristic for the compound studied, suggesting the formation of compound-specific electrophiles. AAF and DMBA adducts were identical to those formed in vivo in animals. Our results show that the Zymbal glands are capable of metabolizing different carcinogens to DNA-reactive intermediates, a process that may be causally associated with tumor formation in vivo in this organ.

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“…32P-postlabeling studies have demonstrated DNA adduct formation in the liver of New Zealand rabbits74) and in the bone marrow of B6C3Fi mice 75) treated with benzene ; however, Reddy et al [76][77][78] were unable to detect the formation of DNA adducts in various tissues of either Sprague-Dawley rats or B6C3Fi mice administered benzene or its hydroxylated metabolites.…”

Section: Genotoxicity (Mutagenicity)mentioning

confidence: 99%